Seventh-seed Federer, a 17-time Grand Slam winner whose run of five US Open titles in a row was halted by Del Potro in the 2009 final, was Thursday drawn into the same quarter as second seed Nadal, a 12-time Grand Slam winner who completed a career Slam with a 2010 US Open title.
The top-ranked potential semi-final rivals for either Spaniard Nadal or Swiss star Federer would be Spanish fourth seed David Ferrer or French eighth seed Richard Gasquet.
In the other half of the draw, Serbia's Djokovic, the reigning Australian Open champion and the 2011 US Open winner, has a tough path to the September 9 men's final that would include a last-eight matchup against Argentina's Del Potro.
Djokovic might then have a semi-final against defending champion and third seed Andy Murray of Britain just to reach the final, with Murray's highest-ranked opponent in his quarter being Czech fifth seed Tomas Berdych.
On the women's side, world number one and top seed Serena Williams could face eighth seed Angelique Kerber in the quarter-finals and either Polish third seed Agnieszka Radwanska or Chinese fifth seed Li Na in the semi-finals.
In the other half of the women's draw, second seed Victoria Azarenka of Belarus and Czech seventh seed Petra Kvitova were drawn into the same quarter of the field with possible opponents in the semi-finals including Italian fourth seed Sara Errani, a 2012 US Open semi-finalist, and Danish sixth seed Caroline Wozniacki.